CN115417816A - Preparation method of 3,6-dibromo-1-chloro-isoquinoline - Google Patents
Preparation method of 3,6-dibromo-1-chloro-isoquinoline Download PDFInfo
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- ZZAYRMTWLXJWLQ-UHFFFAOYSA-N ClC1=NC(Br)=CC2=CC(Br)=CC=C12 Chemical compound ClC1=NC(Br)=CC2=CC(Br)=CC=C12 ZZAYRMTWLXJWLQ-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkali metal alkoxide Chemical class 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 239000012320 chlorinating reagent Substances 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- KSONICAHAPRCMV-UHFFFAOYSA-N 5-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2C(=O)CCC2=C1 KSONICAHAPRCMV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical group ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000012512 characterization method Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 229910020656 PBr5 Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
Abstract
A preparation method of 3,6-dibromo-1-chloro-isoquinoline, which belongs to the field of organic synthesis and comprises the following steps:
Description
Technical Field
The invention relates to the field of organic synthesis, and in particular relates to a preparation method of 3,6-dibromo-1-chloro-isoquinoline.
Background
3,6-dibromo-1-chloro-isoquinoline is a key intermediate in the synthesis process of OLED molecular materials. The existing 3,6-dibromo-1-chloro-isoquinoline synthesis method has the disadvantages of more general process steps, complex process, lower yield of target products and more byproducts. How to develop a 3,6-dibromo-1-chloro-isoquinoline synthesis method with simple process, high yield and less side reactions is a difficult problem which is eagerly solved in the industry.
Disclosure of Invention
In order to solve the problems in the prior art, the invention designs a new route for synthesizing 3,6-dibromo-1-chloro-isoquinoline, and the new route has the advantages of simple process, mild conditions, high yield and few side reactions, and is suitable for industrial production.
The technical scheme of the invention is as follows:
a preparation method of 3,6-dibromo-1-chloro-isoquinoline (I),
which comprises the following steps:
s1, weighing 5-bromo-1-indanone W001, dissolving in an alcohol solvent, slowly adding concentrated hydrochloric acid, dropwise adding nitrite or nitrite at about 30-50 ℃, uniformly stirring, reacting at about 30-50 ℃, cooling to room temperature after reaction, and filtering to obtain white floccule W002
S2, dissolving a compound W002 in a halogenated hydrocarbon solvent, introducing HCl gas in advance to prepare a saturated solution, adding a brominating reagent in batches at the temperature of about 0 ℃, uniformly stirring, reacting at the temperature of about 70-90 ℃, and performing post-treatment after the reaction to obtain a compound W003
S3, dissolving the compound W003 in a sodium methoxide/alcohol solvent or an alkali metal alkoxide/hydrocarbon solvent, uniformly stirring, reacting at 50-85 ℃, and carrying out post-treatment after the reaction to obtain solid W004
Wherein R is an alkyl group, such as C1-C6 alkyl, methyl, ethyl, propyl, butyl or tert-butyl;
s4, dissolving the crude product of the compound W004 in a halogenated hydrocarbon solvent, adding Lewis acid below 0 ℃ for reaction at room temperature, quenching the reaction by using a saturated alkali solution at 0 ℃ after the reaction is finished, and performing post-treatment to obtain solid W005
S5, dissolving W005 in a chlorinating agent, uniformly stirring, reacting at the temperature of about 100 ℃ to about 130 ℃, cooling to room temperature after the reaction is finished, distilling under reduced pressure to remove the chlorinating agent, and carrying out post-treatment to obtain a white solid
In some embodiments, the nitrite or nitrite ester in step S1 is selected from sodium nitrite, isobutyl nitrite, tert-butyl nitrite, and like agents.
In some embodiments, the molar ratio of the brominating reagent to compound W002 in S2 step is about 2.0 to about 5.0, and in some embodiments, the molar ratio of the brominating reagent to compound W002 is about 3.0. In some embodiments, the brominating reagent is selected from POBr 3 Or PBr 5 。
In some embodiments, the halogenated hydrocarbon solvent in step S2 or step S4 is selected from one or more of dichloroethane DCE, dichloromethane, carbon tetrachloride, or 1,2-dichloroethane.
In some embodiments, the S2 step post-processing comprises: cooling to room temperature, concentrating under reduced pressure and carefully pouring the residue into a mixture of ice and water to quench, filtering, extracting the filtrate with ethyl acetate, drying, concentrating, and purifying with a column to give a grey solid W003
In some embodiments, the alcoholic solvent of step S3 is selected from methanol, ethanol, isopropanol, tert-butanol, or a combination thereof; the alkali metal alkoxide/aprotic solvent is selected from potassium t-butoxide, sodium methoxide, sodium isopropoxide or a similar active base or a combination thereof, and the aprotic solvent is selected from benzene, toluene, xylene or a combination thereof, and in some embodiments, the alkali metal alkoxide/aprotic solvent is a combination of toluene and t-Bu 0K.
In some embodiments, in step S4, the lewis acid is selected from PCl 3 、BBr 3 、AlCl 3 、BF 3 Or BCl 3 Or a combination thereof; the chlorinating agent is selectedself-POCl 3 、PCl 5 。
In some embodiments, the amount of alkali metal alkoxide used in the process may be in an equivalent (molar) or excess (molar) relative to the compound of formula (W003), and in some embodiments, from 1 to 5 equivalents. And in other embodiments from 2 to 5 equivalents. In other embodiments from 3 to 5 equivalents, and in certain embodiments from 1.1 to 2.5 equivalents.
In some embodiments, the S1 step reaction temperature is about 35 ℃ or about 40 ℃, or about 45 ℃, or about 50 ℃; the reaction temperature in the step S2 is about 75 ℃, or about 78 ℃, or 80 ℃, or about 85 ℃; the reaction temperature of the S3 step is 55 ℃, or about 60 ℃, or about 65 ℃, or about 70 ℃, or about 75 ℃; the reaction temperature of the S4 step is about 20 ℃, or about 25 ℃, or about 30 ℃, or about 32 ℃, or about 35 ℃; the reaction temperature in the step S4 is about 110 ℃ or about 115 ℃, or about 120 ℃ or about 130 ℃ or about 135 ℃.
The methods described herein may also include known purification methods such as crystallization, chromatography (liquid and gas phases and the like), extraction, distillation, trituration, and reverse phase HPLC, among others. The reaction conditions such as temperature, reaction time, pressure and gas (e.g., inert gas, air) may be appropriately adjusted depending on the reaction.
The invention has the advantages that:
the invention adopts a brand new synthesis route to synthesize 3,6-dibromo-1-chlorine-isoquinoline (I), and related intermediates are all solid, so that the post-treatment is simple and convenient, and the method is suitable for industrial production; the total yield of five steps is up to more than 30%.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The starting materials and reagents used in the present invention can be prepared by known methods or can be commercially available.
Example 1 a method of making 3,6-dibromo-1-chloro-isoquinoline includes the steps of:
s1, weighing 5-bromo-1-indanone W001 (500g, 2369mmol) and dissolving inMeOH (4500 mL), then con. HCI (213 mL) was added slowly, butyl nitrite (308.3 mL) was added dropwise at 40 ℃, stirred well and reacted for 2.5h at 40 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered to obtain W002 (421 g, yield 59.07%) as a white floc. Characterization of W002 results 1H NMR (400mhz, dmso-d 6) δ 12.73 (s, 1H), 7.90 (p, J =1.1hz, 1h), 7.68 (d, J =1.1hz, 2h), 3.79 (d, J =1.0hz, 2h), MS (ESI) m/z:239.97[ 2 ], [ C ] 9 H 6 BrNO 2 + H] + .
S2, taking W002 (23.9g, 100mmol) to dissolve in DCE (500 mL, prepared into saturated solution by introducing HCl gas in advance), and adding POBr in portions at 0 DEG C 3 (60g, 200mmol), stirring well and reacting at 80 ℃ for 2h. After cooling to room temperature, concentration under reduced pressure and careful pouring of the residue into a mixture of ice and water to quench, after filtration the filtrate was extracted with ethyl acetate, dried, concentrated and after column purification afforded W003 (22.1 g, yield 61%) as a grey solid. Characterization of W003 results 1H NMR (400mhz, dmso-d 6) 68.34 (d, J =2.0hz, 1h), 8.24 (d, J =0.8hz, 1h), 8.10 (dt, J = 9.1,0.7hz, 1h), 7.97 (dd, J =9.0,1.9hz, 1h). MS (ESI) m/z:363.80[ C ] 9 H 4 Br 3 N + H] + .
S3, W003 (0.365g, 1mmol) was dissolved in MeOH (2 mL), and sodium methoxide (0.27g, 5mmol) was added thereto, and the mixture was stirred uniformly and reacted at 70 ℃ for 2 hours. After cooling to room temperature the MeOH was distilled off under reduced pressure and the resulting residue was extracted with ethyl acetate, washed once with water and saturated brine respectively, the organic phase was dried, filtered and concentrated to give W004 (0.25 g, crude product) as a brown solid. Characterization of W004 results 1H NMR (400mhz, chloroform-d) 68.07 (dt, J =8.8, 0.7hz, 1h), 7.83 (d, J =1.9hz, 1h), 7.63 (dd, J =8.9,1.9hz, 1h), 7.37 (d, J =0.8hz, 1h), 7.29 (s, 1H), 4.16(s，3H).MS(ESI)m/z：315.90[C 10 H 7 Br 2 NO + H] + .
S4, taking W004 (0.25 g, crude product) and dissolving in CH 2 Cl 2 (2 mL), BBr was added at 0 deg.C 3 (2 mL) and reacted at room temperature for 1h. After the reaction, a saturated sodium bicarbonate solution was added at 0 ℃ to quench the reaction, and the reaction solution was diluted with dichloromethane, extracted with a saturated saline solution, dried, filtered, and concentrated to obtain a brown yellow solid W006 (0.2 g, crude product). Characterization results MS (ESI) m/z:301.88[ 2 ], [ C ] 9 H 5 Br 2 NO + H] + .
S5, dissolving W006 (17g, 56.5mmol) in POCl 3 (60 mL), stirred well and reacted at 120 ℃ for 2h. Cooling to room temperature, and distilling under reduced pressure to remove POCl 3 The obtained residue was extracted with ethyl acetate, washed with saturated brine and saturated aqueous sodium bicarbonate solution, respectively, and the organic phase was dried, filtered, concentrated, and column-purified to obtain OLED2 (11.75 g, yield 64.02%, purity 98.5%, HPLC purity) as a white solid. Characterization results for OLED2 1H NMR (500mhz, dmso-d 6) δ 8.38 (d, J =2.0hz, 1h), 8.25 (d, J =0.8hz, 1h), 8.19 (d, J =9.0hz, 1h), 7.99 (dd, J =9.0,1.9hz, 1h). MS (ESI) m/z:319.85[ 2 ], [ C ] 9 H 4 Br 2 CIN + H] + .
Example 2 a method of making 3,6-dibromo-1-chloro-isoquinoline includes the steps of:
s1 is the same as step S1 in example 1.
S2 is the same as step S2 in example 1.
S3, dissolving W003 (0.732g, 2mmol) in toluene (5 mL), adding t-BuOK (0.56g, 5mmol) at 0 ℃, stirring uniformly, reacting at 110 ℃ for 2H, cooling to room temperature, concentrating under reduced pressure, extracting the obtained residue with ethyl acetate, drying, filtering, concentrating, and purifying with a column to obtain W005 (0.4 g, yield 56%) as a yellow solid, W005 (400MHz, DMSO-d 6), delta 8.14 (d, J =1.9Hz, 1H), 8.00 (dt, J =8.9,0.7Hz, 1H), 7.75 (dd, J =8.9,2.0Hz, 1H), 7.63 (d, J =0.8Hz, 1H), 1.67 (S, 10H), MS (ESI) m/z:357.94 [ C.5363 [ [ C, 10H ] ], ] 13 H 13 Br 2 NO + H] + .
S4, W005 (0.183g, 0.5 mmol) was dissolved in HCOOH (3 mL) and reacted at room temperature for 0.5h. After completion of the reaction, the solvent was directly removed by concentration, and the residue was purified by column chromatography to obtain W006 as a yellow solid (0.1 g, yield 66%). Characterization results MS (ESI) m/z:301.88[ 2 ], [ C ] 9 H 5 Br 2 NO + H] + .
Example 3 a method of making 3,6-dibromo-1-chloro-isoquinoline includes the steps of:
s1 is the same as step S1 in example 1.
S2, taking W002 (23.9g, 100mmol) to dissolve in dried dichloromethane (1L), adding PBr5 (64.57 g, 150mmol) at 0 ℃, stirring uniformly, and reacting for 16h at 30 ℃. The dichloromethane was removed by concentration under reduced pressure, the obtained residue was redissolved with dioxane (1L), dried at 10 ℃ to obtain HBr gas, the gas was stopped when the reaction solution changed from beige to brown, reacted at 30 ℃ for 16 hours, and then reacted at 60 ℃ for 2 hours. Cooling the reaction solution to room temperature, extracting with ethyl acetate, washing with saturated saline water and saturated sodium bicarbonate water solution, drying the organic phase, filtering, concentrating, and pulping with n-hexane to obtain brown yellowW006 as a colored solid (17 g, 56.5% yield). Characterization of W006 results 1H NMR (500 mhz, dmso-d 6) δ 12.35 (s, 1H), 8.04 (d, J =8.5hz, 1h), 7.91 (d, J =2.0hz, 1h), 7.65 (dd, J =8.5, 2.0hz, 1h), 6.88 (s, 1H). MS (ESI) m/z:301.88[ 2 ], [ C ] 9 H 5 Br 2 NO+H]+.
S3 is the same as step S5 in example 1.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of 3,6-dibromo-1-chloro-isoquinoline (I),
which comprises the following steps:
s1, weighing 5-bromo-1-indanone W001, dissolving in an alcohol solvent, slowly adding concentrated hydrochloric acid, dropwise adding nitrite or nitrite at about 30-50 ℃, uniformly stirring, reacting at about 30-50 ℃, cooling to room temperature after reaction, and filtering to obtain white floccule W002
S2, dissolving a compound W002 in a halogenated hydrocarbon solvent, introducing HCl gas in advance to prepare a saturated solution, adding a brominating reagent in batches at the temperature of about 0 ℃, uniformly stirring, reacting at the temperature of about 70-80 ℃, and performing post-treatment after the reaction to obtain a compound W003
S3, dissolving the compound W003 in an alcohol solvent/sodium methoxide or alkali metal alkoxide/hydrocarbon solvent, uniformly stirring, reacting at 50-85 ℃, and treating after the reaction is finished to obtain solid W004
Wherein R is an alkyl group, such as C1-C6 alkyl, methyl, ethyl, propyl, butyl or tert-butyl;
s4, dissolving the crude product of the compound W004 in a halogenated hydrocarbon solvent, adding Lewis acid below 0 ℃ for reaction at room temperature, quenching the reaction by using a saturated alkali solution at 0 ℃ after the reaction is finished, and performing post-treatment to obtain solid W005
S5, dissolving W005 in a chlorinating agent, uniformly stirring, reacting at the temperature of about 100 ℃ to about 130 ℃, cooling to room temperature after the reaction is finished, distilling under reduced pressure to remove the chlorinating agent, and carrying out post-treatment to obtain a white solid
2. The method according to claim 1, wherein said nitrite or nitrite ester in step S1 is selected from the group consisting of sodium nitrite, isobutyl nitrite, and tert-butyl nitrite.
3. The method according to claim 1, wherein the molar ratio of the brominating reagent to the compound W002 in the S2 step is 2.0 to 5.0.
4. A method according to claim 3 wherein the molar ratio of said brominating reagent to compound W002 is 3.0.
5. The process according to claim 3 or 4, wherein the brominating reagent is POBr 3 Or PBr 5 。
6. The method according to claim 1, wherein the halogenated hydrocarbon solvent in step S2 or S4 is one or more selected from the group consisting of dichloroethane DCE, dichloromethane, carbon tetrachloride and 1,2-dichloroethane.
7. The method of claim 1, wherein the step S2 post-processing comprises: after cooling to room temperature, concentration under reduced pressure and quenching by careful pouring of the residue into an ice-water mixture, filtration and extraction of the filtrate with ethyl acetate, drying, concentration and column purification gave W003 as a grey solid.
8. The method according to claim 1, wherein the alcoholic solvent in step S3 is selected from methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.
9. The method of claim 1, wherein the alkali metal alkoxide/aprotic solvent is selected from potassium t-butoxide, sodium methoxide, sodium isopropoxide, or a similar active base or a combination thereof, and the aprotic solvent is selected from benzene, toluene, xylene, or a combination thereof, or the alkali metal alkoxide/aprotic solvent is a combination of toluene and t-BuOK.
10. The method according to claim 1, wherein the Lewis acid is selected from PCl in step S4 3 、BBr 3 、AlCl 3 、BF 3 Or BCl 3 Or a combination thereof; the chlorinating agent is selected from POCl 3 Or PCl 3 。
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| CN115572262A (en) * | 2022-10-27 | 2023-01-06 | 厦门沃克沃德医药科技有限公司 | Isoquinoline derivative and preparation method thereof |
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